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Overview

Motoneuron Influences on Muscle Atrophy in Simulated Microgravity Induced Muscle Atrophy

Principal Investigator:
Dennis R. Mosier, M.D., Ph.D.

Organization:
Baylor College of Medicine

NASA Taskbook Entry

Technical Summary

Many alterations in motor unit structure and function occur with exposure to microgravity during spaceflight, and could impair motor performance. While much work is ongoing to ascertain the nature of biochemical, structural, and physiological changes occurring in muscle fibers, little attention has been paid to the changes reported in motoneuron terminals at the skeletal neuromuscular junction, and in motoneuron cell bodies, during exposure to microgravity. It is unlikely that these changes, whether they occur independently or secondary to changes in the innervated muscle fibers, are without consequences for the regulation of motor unit function. Accordingly, the central hypothesis of this study is that alterations in motoneuron structure and function occur during the process of microgravity-induced muscle atrophy, and that these alterations significantly influence muscle dysfunction, adaptation, and recovery from atrophy induced by microgravity. These changes may be manifested as early structural and functional alterations in the distal motoneuron terminal, in addition to alterations in motoneuron activity produced by changes in stretch reflexes and supraspinal pathways. Initiation of alterations in motoneuron terminals may be influenced by retrograde signals from muscle which induce, as an early event, changes in intracellular calcium and transmitter release. To begin to address these hypotheses, a combination of electrophysiologic assays of transmitter release at neuro-muscular junctions, coupled with electron microscopic assays of junctional remodelling, synaptic vesicles, and intraterminal calcium, is being used to define quantitatively the nature, extent, and possible significance of changes in motoneuron terminals occurring in a mouse model of unloading-induced muscle atrophy.

During the course of this work, a technique for S-SFEMG (stimulated single-fiber electromyography) was adapted and validated for mice, allowing in vivo measurements of neuromuscular transmission. Data from this work suggest that: (1) unloading of skeletal muscle is associated with altered transmitter release at neuromuscular junctions, ultrastructural abnormalities, and a reduced safety factor suggesting insecure neuromuscular transmission; (2) the extent and nature of these junctional alterations vary among individual hind-limb muscles, possibly relating to differences in muscle loading and/or fiber type composition; (3) the extent of junctional alterations varies with duration of hind-limb unloading; (4) unloading of skeletal muscle may be associated with increased calcium in the motoneuron terminal, which may act as a signal inducing the observed junctional alterations; and (5) altered neuromuscular junctions in unloaded muscle retain the insensitivity to acute muscle stretch typical of normal mammalian junctions. Based on our observations, we hypothesize that junctional remodeling associated with muscle atrophy may vary over time, and may, especially in combination with other physiological stresses encountered during spaceflight (e.g., hypothermia, medication effects), pose a risk of junctional transmission failure. In the mouse hind-limb unloading model, we were unable to reproduce the full range of ultrastructural changes reported in studies of space-flown animals, and therefore suggest that additional factors (especially reloading injury and/or eccentric contraction injury of atrophied muscle) may have contributed to this disparity. Our evidence to date suggests that transgenic over-expression of IGF-1 in skeletal muscle, which can induce junctional alterations in some systems and is proposed as a potential countermeasure for unloading-induced muscle atrophy, does not exacerbate junctional alterations in this model system. Finally, our preliminary data indicating alteration of intracellular calcium and of calcium-dependent processes within motoneuron terminals suggest the possibility of increasing calcium-binding protein expression as a potential countermeasure for the observed alterations of neuromuscular junctions with hind-limb unloading.

Our comprehensive approach using electrophysiologic and ultrastructural techniques is being extended to determine the junctional effects and tolerability of transgenic overexpression of a calcium-binding protein, parvalbumin, and to determine whether parvalbumin overexpression can ameliorate motoneuron dysfunction and/or muscle atrophy in mouse models of muscle atrophy and of neuromuscular diseases. Data obtained from this study will be useful in defining the anatomic and physiologic consequences to motoneurons of manipulations which induce muscle atrophy, and will aid in designing further experiments to determine the mechanisms influencing motor unit dysfunction occurring during space travel. Information from this study will be of value to the design and refinement of countermeasures aimed at ameliorating the deleterious effects of microgravity on human motor performance. The results of this work may also provide new insights into important clinical problems such as mechanisms influencing motoneuron dysfunction in devastating degenerative illnesses such as amyotrophic lateral sclerosis, muscle and motor nerve injury encountered in critical care settings, and the design of therapies to retard or prevent muscle atrophy produced by disuse or spinal cord injury.

This project's funding ended in 2000